RT Journal Article SR Electronic T1 cAMP and Extracellular Signal-Regulated Kinase Signaling in Response to d-Amphetamine and Methylphenidate in the Prefrontal Cortex in Vivo: Role of β1-Adrenoceptors JF Molecular Pharmacology JO Mol Pharmacol FD American Society for Pharmacology and Experimental Therapeutics SP 421 OP 429 DO 10.1124/mol.105.011809 VO 68 IS 2 A1 Vincent Pascoli A1 Emmanuel Valjent A1 Anne-Gaëlle Corbillé A1 Jean-Christophe Corvol A1 Jean-Pol Tassin A1 Jean-Antoine Girault A1 Denis Hervé YR 2005 UL http://molpharm.aspetjournals.org/content/68/2/421.abstract AB d-Amphetamine and methylphenidate are widely used in the treatment of attention-deficit/hyperactivity disorder. Both drugs increase extracellular norepinephrine and dopamine in the prefrontal cortex, where they are believed to exert their therapeutic effects. However, the molecular mechanisms underlying their action are poorly understood. To investigate the intracellular signaling pathways activated by d-amphetamine and methylphenidate in the prefrontal cortex in vivo in mice, we measured the cAMP-dependent Ser845 phosphorylation of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor GluR1 subunit and the active form of extracellular signal-regulated kinase (ERK). Administration of d-amphetamine (5–10 mg/kg) or methylphenidate (10–20 mg/kg) increased phosphorylation of GluR1. Basal and d-amphetamine–induced GluR1 phosphorylation was reduced by propranolol, a general β-adrenoceptor antagonist, and betaxolol, a β1-antagonist, but not by (±)-1-[2,3-(dihydro-7-methyl-1H-inden-4-yl)oxy]-3-[(1-methylethyl)amino]-2-butanol (ICI-118,515), a β2-antagonist. The effect of methylphenidate was also blocked by propranolol and betaxolol. The d-amphetamine effect was slightly potentiated by prazosin, an α1-adrenoceptor antagonist, and mimicked by yohimbine, an α2 antagonist. Blockade of dopamine or N-methyl-d-aspartate (NMDA) receptors or serotonin depletion had no effect on d-amphetamine–induced GluR1 phosphorylation. d-amphetamine but not methylphenidate increased ERK phosphorylation. This effect required multiple signaling pathways because it was blocked by β1- and α1-adrenoceptor antagonists, by dizocilpine maleate (MK801), an NMDA antagonist, and by serotonin depletion. In contrast, blockade of dopamine receptors had no effect on d-amphetamine–induced ERK phosphorylation. Propranolol and betaxolol increased the hyperlocomotion produced by d-amphetamine and methylphenidate. Thus, both d-amphetamine and methylphenidate potently activate the cAMP pathway in the prefrontal cortex through β1-adrenergic receptors. This activation could have behavioral consequences and contribute to the treatment of attention-deficit/hyperactivity disorder.